N-benzylhydroxylamine;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-benzylhydroxylamine hydrochloride (13.59 g, 85.15 mmol) and sodium acetate (9.31 g, 114 mmol) were stirred together in ethanol (75 mL) at rt for 15 mins. Aqueous 37% formaldehyde solution (12.68 ml, 170 mmol) was added and stirring continued for 30 mins, then cis-2-butene-1,4-diol (4.67 ml, 56.8 mmol) added and the mixture heated under reflux for 16 h. The solvent was evaporated and the residue dissolved in CHCl3 and washed with aq. sat. NaHCO3, dried (MgSO4) and the solvent evaporated to give a brown syrup suitable for use without further purification (12.5 g, 98%). An aliquot was purified by chromatography on silica gel (EtOAc then EtOAc-MeOH, 95:5) to give ((4RS,5RS)-2-benzylisoxazolidine-4,5-diyl)dimethanol as a colourless syrup. 13C NMR (CDCl3, referenced to the centre line of CDCl3 at 77.0 ppm) δ 136.5, 129.0, 128.4, 127.6, 78.5, 62.4, 61.3, 60.4, 56.8, 45.8. the mixture heated under reflux for 16 h The solvent was evaporated the residue dissolved in CHCl3 washed with aq. sat. NaHCO3 dried (MgSO4) the solvent evaporated to give a brown syrup suitable for use without further purification (12.5 g, 98%) An aliquot was purified by chromatography on silica gel (EtOAc

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (+)-(2R*-3R*)-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylic acid (65 mg, 0.17 mmol) (from Example 20), is added benzylhydroxylamine hydrochloride (32 mg, 0.20 mmol), dicyclohexylcarbodiimide (41 mg, 0.20 mmol) and dimethylaminopyridine (27 mg, 0.22 mmol). The resulting mixture is stirred overnight, diluted with ethyl acetate and filtered through Celite™ and evaporated. The crude product is purified by chromatography elution with 1:1 hexane-ethyl acetate to provide (+)-(2R*-3R*)-N-benzyloxy-1-4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6-tetrahydropyridine-2-carboxamide. filtered through Celite™ evaporated The crude product is purified by chromatography elution with 1:1 hexane-ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of COMPOUND 249 (0.115 g, 0.37 mmol) in toluene (4 mL) was added DIPEA (0.16 mL, 0.92 mmol) followed by phosgene solution (20% in toluene, 0.20 mL, 0.44 mmol). The resultant mixture was stirred at room temperature for 90 minutes then concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and treated with DIPEA (0.60 mL, 3.44 mmol) followed by N-benzylhydroxylamine hydrochloride (0.194 g, 1.22 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (15 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 131 mg (74%) of COMPOUND 272 as a white solid. 1H NMR (CDCl3) δ 1.64-1.76 (m, 2H), 1.918-1.96 (m, 2H), 2.08 (s, 6H), 2.68-2.79 (m, 3H), 3.81 (s, 4H), 4.20 (d, 2H, J=13.2 Hz), 4.30 (s, 2H), 6.81 (s, 1H), 7.08 (dd, 2H, J=7.5, 4.8 Hz), 7.27-7.38 (m, 7H), 8.32 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.35, 27.54, 46.12, 54.86, 57.74, 59.70, 122.87, 127.94, 128.68, 129.35, 133.88, 136.61, 138.59, 146.15, 157.28, 164.68; ES-MS m/z 460 (M+H). Anal. Calcd. For C27H33N5O2.0.2CH2Cl2: C, 68.55; H, 7.06; N, 14.70. Found: C, 68.85; H, 7.21; N, 14.79. then concentrated under reduced pressure The residue was dissolved in DMF (4 mL) The mixture was concentrated the residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (15 mL) The phases were separated the aqueous phase was extracted with CH2Cl2 (3×15 mL) The combined organic extracts were dried (Na2SO4) concentrated Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of COMPOUND 249 (0.115 g, 0.37 mmol) in toluene (4 mL) was added DIPEA (0.16 mL, 0.92 mmol) followed by phosgene solution (20% in toluene, 0.20 mL, 0.44 mmol). The resultant mixture was stirred at room temperature for 90 minutes then concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and treated with DIPEA (0.60 mL, 3.44 mmol) followed by N-benzylhydroxylamine hydrochloride (0.194 g, 1.22 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (15 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 131 mg (74%) of COMPOUND 272 as a white solid. 1H NMR (CDCl3) δ 1.64-1.76 (m, 2H), 1.918-1.96 (m, 2H), 2.08 (s, 6H), 2.68-2.79 (m, 3H), 3.81 (s, 4H), 4.20 (d, 2H, J=13.2 Hz), 4.30 (s, 2H), 6.81 (s, 1H), 7.08 (dd, 2H, J=7.5, 4.8 Hz), 7.27-7.38 (m, 7H), 8.32 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.35, 27.54, 46.12, 54.86, 57.74, 59.70, 122.87, 127.94, 128.68, 129.35, 133.88, 136.61, 138.59, 146.15, 157.28, 164.68; ES-MS m/z 460 (M+H). Anal. Calcd. For C27H33N5O2.0.2CH2Cl2: C, 68.55; H, 7.06; N, 14.70. Found: C, 68.85; H, 7.21; N, 14.79. then concentrated under reduced pressure The residue was dissolved in DMF (4 mL) The mixture was concentrated the residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (15 mL) The phases were separated the aqueous phase was extracted with CH2Cl2 (3×15 mL) The combined organic extracts were dried (Na2SO4) concentrated Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-benzylhydroxylamine hydrochloride (0.77 g, 4.82 mmol) and triethylamine (0.76 mL, 5.45 mmol) were successively added to a solution of (E)-ethyl 3-cyclobutylacrylate, 46a, (0.65 g, 4.19 mmol) in dry dichloromethane (23.5 mL). The reaction mixture was allowed to stir at room temperature under an atmosphere of nitrogen for 3 days. The mixture was diluted with 75 mL of water and the layers were separated. The aqueous phase was reextracted twice more with dichloromethane (50 mL). The combined organic phases were dried over MgSO4, filtered and evaporated to dryness. The residue was purified via silica gel chromatography (0-100% EtOAc/Hexanes gradient) to afford 834 mg (86%) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m, 5H), 4.64 (s, 1H), 3.82 (q, J=13.5 Hz, 2H), 3.37-3.18 (m, 1H), 2.80-2.52 (m, 2H), 2.33 (dd, J=14.5, 5.1 Hz, 1H), 2.22-2.09 (m, 1H), 2.01-1.68 (m, 5H). the layers were separated The combined organic phases were dried over MgSO4 filtered evaporated to dryness The residue was purified via silica gel chromatography (0-100% EtOAc/Hexanes gradient)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure described in Tetrahedron 55, 1999, 4685-4698, N—BOC-allylamine (2 g) was dissolved in toluene (130 ml) and ethanol (45 ml) then benzylhydroxylamine hydrochloride (3.05 g), paraformaldehyde (3.16 g) and triethylamine (1.93 g) were added. The reaction mixture was allowed to stir at room temperature for 24 hours, then the solvent was evaporated in vacuo. The resulting residue was diluted in ethyl acetate and the hydrochloride salt of triethylamine was filtered off. The filtrate was concentrated in vacuo and the residue purified by column chromatography (ethyl acetate/cyclohexane 1:1) to afford the title compound as a colorless oil (4.37 g). LCMS (Method F) 1.53 min, M+H 293. the solvent was evaporated in vacuo The resulting residue was diluted in ethyl acetate the hydrochloride salt of triethylamine was filtered off The filtrate was concentrated in vacuo the residue purified by column chromatography (ethyl acetate/cyclohexane 1:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound is prepared by coupling of 9-(3-chloro-2,6-difluorobenzyl)-9H-β-carboline-3-carboxylic acid and N-benzyl hydroxylamine hydrochloride under conditions similar to those provided in step (b) of example 7. those provided in step (b) of example 7

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using the procedure of Example 1, the title compound is prepared from 15.0 g (94 mmol) of N-benzylhydroxylamine hydrochloride, 10.6 g (100 mmol) of benzaldehyde, 26.7 g (100 mmol) of dibenzyl phosphite, 3.78 g (45 mmol) of sodium bicarbonate and 300 ml of THF by heating at 60° C. for four hours. The residue is purified by column chromatography (silica gel, 2.5:1 hexane:ethyl acetate eluent) followed by recrystallization from a mixture of methylene chloride and hexane to give 5.6 g (13% yield) of a white solid melting at 116°-118° C. The residue is purified by column chromatography (silica gel, 2.5:1 hexane:ethyl acetate eluent) followed by recrystallization from a mixture of methylene chloride and hexane

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using the procedure of Example 1, the above-named compound is prepared from 5.0 g (31 mmol) of N-benzylhydroxylamine hydrochloride, 1.8 g (60 mmol) of paraformaldehyde, 3.7 ml (40 mmol) of dimethyl phosphite, 2.5 g (30 mmol) of sodium bicarbonate and 350 ml of THF by heating at 55° C. for seven hours. The residue is purified by column chromatography (silica gel, methylene chloride:ethyl acetate eluent) to give 6.1 g (80% yield) of a viscous colorless liquid. The residue is purified by column chromatography (silica gel, methylene chloride:ethyl acetate eluent)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using the procedure of Example 1, the above-named compound is prepared from 5.0 g (31 mmol) of N-benzylhydroxylamine hydrochloride, 1.8 g (60 mmol) of paraformaldehyde, 3.7 ml (40 mmol) of dimethyl phosphite, 2.5 g (30 mmol) of sodium bicarbonate and 350 ml of THF by heating at 55° C. for seven hours. The residue is purified by column chromatography (silica gel, methylene chloride:ethyl acetate eluent) to give 6.1 g (80% yield) of a viscous colorless liquid. The residue is purified by column chromatography (silica gel, methylene chloride:ethyl acetate eluent)

Conditions: temp:59.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2.0 g (12.5 mmol) of N-benzylhydroxylamine hydrochloride, 0.75 g (25 mmol) of paraformaldehyde, 1.0 g (12 mmol) of sodium bicarbonate and 40 ml of tetrahydrofuran (THF) is stirred at 59° C. for one hour. To the resultant mixture is then added dropwise over a three-hour period a solution of 3.6 g (13.7 mmol) of dibenzyl phosphite in 40 ml of THF. The reaction mixture is then stirred for 14 hours at 55° C. The reaction mixture is concentrated in vacuo to 20 ml volume and 500 ml of ethyl acetate is added. The organic phase is separated and washed sequentially with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic phase is dried over anhydrous magnesium sulfate and the solvent removed in vacuo. The residue is purified by column chromatography (silica gel, 20:1, methylene chloride:ethyl acetate eluent) followed by recrystallization from a mixture of methylene chloride, ethyl acetate and hexane to give 1.95 g (40% yield) of a white solid melting at 62°-64° C. The reaction mixture is then stirred for 14 hours at 55° C The reaction mixture is concentrated in vacuo to 20 ml volume and 500 ml of ethyl acetate is added The organic phase is separated washed sequentially with a saturated solution of sodium bicarbonate The organic phase is dried over anhydrous magnesium sulfate the solvent removed in vacuo The residue is purified by column chromatography (silica gel, 20:1, methylene chloride:ethyl acetate eluent) followed by recrystallization from a mixture of methylene chloride, ethyl acetate and hexane

Conditions: temp:59.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2.0 g (12.5 mmol) of N-benzylhydroxylamine hydrochloride, 0.75 g (25 mmol) of paraformaldehyde, 1.0 g (12 mmol) of sodium bicarbonate and 40 ml of tetrahydrofuran (THF) is stirred at 59° C. for one hour. To the resultant mixture is then added dropwise over a three-hour period a solution of 3.6 g (13.7 mmol) of dibenzyl phosphite in 40 ml of THF. The reaction mixture is then stirred for 14 hours at 55° C. The reaction mixture is concentrated in vacuo to 20 ml volume and 500 ml of ethyl acetate is added. The organic phase is separated and washed sequentially with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic phase is dried over anhydrous magnesium sulfate and the solvent removed in vacuo. The residue is purified by column chromatography (silica gel, 20:1, methylene chloride:ethyl acetate eluent) followed by recrystallization from a mixture of methylene chloride, ethyl acetate and hexane to give 1.95 g (40% yield) of a white solid melting at 62°-64° C. The reaction mixture is then stirred for 14 hours at 55° C The reaction mixture is concentrated in vacuo to 20 ml volume and 500 ml of ethyl acetate is added The organic phase is separated washed sequentially with a saturated solution of sodium bicarbonate The organic phase is dried over anhydrous magnesium sulfate the solvent removed in vacuo The residue is purified by column chromatography (silica gel, 20:1, methylene chloride:ethyl acetate eluent) followed by recrystallization from a mixture of methylene chloride, ethyl acetate and hexane